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Parkinson’s Disease

Parkinson’s Disease. Bradykinesia, tremor, rigidity, postural reflect impairment Destruction of dopaminergic neurons in the pars compacta of the substantia nigra (with Lewy inclusion bodies) Lifetime risk up to 2% men, 1.3% women; rates rising among >75yo.

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Parkinson’s Disease

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  1. Parkinson’s Disease • Bradykinesia, tremor, rigidity, postural reflect impairment • Destruction of dopaminergic neurons in the pars compacta of the substantia nigra (with Lewy inclusion bodies) • Lifetime risk up to 2% men, 1.3% women; rates rising among >75yo

  2. Parkinson’s Disease and the Environment: the Potential Contribution of Metal-Gene Interactions Howard Hu, M.D., M.P.H., Sc.D. Professor of Occupational and Environmental Medicine Harvard School of Public Health

  3. PD causation • Twin studies: must be mostly environmental or gene-env >50yo • Environment • IVDA exposed to MPTP • Pesticides • Paraquat—induces oxygen free radicals leading to lipid peroxidation in neurons • Heptachlor, rontenone, dieldrin—may accelerate alpha-synuclein fibrilformation • Solvents—n-hexane, toluene • Smoking (inverse) • Metals???

  4. PD causation: Metals? • Metals • Manganese—miners, welder, smelters • Mercury—case-control study • Lead—Gorell study: population case-control, occupational exposure to lead—OR of 5.24 (95%CI: 1.59-17); exposure rated by IH blinded to case-control status • Mechanism • Catalyzation of Fenton reaction generating reactive oxygen species • Synergy with iron?

  5. Metals Epidemiology Research Group • Director: Howard Hu • Primary base: • Dept. Environ Health, HSPH (also, Depts. Of Epi, Biostat, Health and Social Behavior, Maternal and Child Health, Cell and Cancer Biology) • Channing Lab, Brigham&Women’s, HMS • Collaborations: • Boston: Boston VA Hospital, Normative Aging Study, BU Neuro, Children’s Hospital, Mass Coll of Pharmacy • Outside: UC-Santa Cruz, NIEHS, U. Pittsburgh, Brookhaven Nat’l Lab, Nat’l Inst. Public Health-Mexico` • Funding:NIEHS, NHLBI, EPA, CDC, ATSDR, NIOSH, March of Dimes

  6. Lead as cause of PD • High population exposures with long-lived body stores • Animal studies: lead decreases dopamine synthesis, turnover, uptake in the basal ganglia • Increased spontaneous release of dopamine; dopamine auto-oxidized to 6-OHDA, facilitating Fenton reaction; places these neurons at increased risk of oxidative toxicity • Lead also has direct oxidative properties, perhaps mediated by ALA

  7. Our relevant prior research • We have developed and used a new biological marker of cumulative lead dose to elucidate lead’s impact on chronic disease • We have also examined other lead-gene interactions • Examples…

  8. Method for measuring cumulative lead exposure: scanning measurements of bone lead using K-x-ray fluorescence • Non-invasive • Safe (radiation dose in microsieverts) • Convenient (20-30 minutes/measure)

  9. Hu et al. (JAMA, 1996). Bone lead and odds of hypertension in the Normative Aging Study.* 2 1.8 1.6 1.4 1.2 1 0.8 Odds of developing 0.6 0.4 hypertension 0.2 0 Lowest Highest quartile quartile

  10. Cheng et al. (Am J Epi, 2001). Bone lead and prospective rate ratio of developing hypertension in the Normative Aging Study.* 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 Low bone High bone Rate ratio of lead lead hyperension

  11. Cheng et al. (Am J Cardiology, 1998). Bone lead and EKG conduction in the NAS.* 0.25 0.2 0.15 0.1 0.05 0 QT QRS Low bone lead interval interval High bone lead (ms)

  12. Korrick et al. (Am J Public Health, 1999). Bone lead and hypertension in nurses.* 2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 Odds of developing Lowest Highest hypertension quartile quartile

  13. Payton et al., 1998 (Neurotox and eratology) Bone lead and cognition in the NAS 10 9 8 Low bone lead 7 6 5 4 High bone lead 3 2 1 0 Constructional Pattern Memory, Praxis Score Seconds to Complete

  14. Kamel et al., 2002 (Epidemiology): Case Control study of ALS and Lead 4 3.5 3 2.5 2 1.5 1 0.5 0 OR for Low bone lead developing High bone lead ALS

  15. Wu et al., (EHP, 2003). Increase in serum creatinine (mg/dL) assoc. with bone lead of 40 μg/g, stratified by ALAD genotype* (Conclusion: ALAD-2 gene carriers have worse kidney toxicity from lead). 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 ALAD 1-1 0 ALAD 1-2/2-2 1st Qtr

  16. Candidate genes for gene-metal interactions and Parkinson’s • HFE—hemochromatosis (C282Y, H63D) • Increases intracellular iron that can • catalyze reactions to produce toxic-free radicals • promote the Fenton reaction

  17. Our Study Design: Case Control Epidemiologic Study • NIEHS R01ES10798 to Channing Lab, 5 yrs • Major collaboration with the late R. Feldman, Marie St-Hilaire, and BU-PDC • Existing PD patients (n=1,233) + new PD patients (n=1,080) • Critieria: PD sx<10y, meet case def, within 2 hrs drive • Controls: spouses and in-laws

  18. Case definition • Complete hx and clinical eval by neurol • 2 of 3: resting tremor, cogwheel rigidity, bradykinesia • Assymetry • None of: [supranuclear gaze palsy, postural instability, dysautonomia] out of proportion for PD; unexplained [cerebellar findings, hyperreflexia]; no response to L-dopa; nonprogressive; MRI or CT with infarcts • Recent clinical exam, with at least 2 exams • Sx < 10 yrs

  19. Protocol • Questionnaire (exposures, smoking, diet, etc) • KXRF measures of bone lead, blood lead • Toenails for manganese, copper • Blood for genotyping of HFE status and for future genotyping, other studies

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